title: Cystic fibrosis transmembrane regulator correctors and potentiators.
abstract: Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, a cAMP-regulated anion channel expressed primarily at the apical plasma membrane of secretory epithelia. Nearly 2000 mutations in the CFTR gene have been identified that cause disease by impairing its translation, cellular processing, and/or chloride channel gating. The fundamental premise of CFTR corrector and potentiator therapy for CF is that addressing the underlying defects in the cellular processing and chloride channel function of CF-causing mutant CFTR alleles will result in clinical benefit by addressing the basic defect underlying CF. Correctors are principally targeted at F508del cellular misprocessing, whereas potentiators are intended to restore cAMP-dependent chloride channel activity to mutant CFTRs at the cell surface. This article reviews the discovery of CFTR potentiators and correctors, what is known regarding their mechanistic basis, and encouraging results achieved in clinical testing.
authors.affiliation: Department of Medicine, Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Alabama 35294, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rowe
authors.forename: Alan S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000627:Aminophenols / Q000627:therapeutic use; D000631:Aminopyridines / Q000627:therapeutic use; D001499:Bayes Theorem; D052117:Benzodioxoles / Q000627:therapeutic use; D018118:Chloride Channels / Q000235:genetics; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000187:drug effects / Q000235:genetics*; D055808:Drug Discovery; D006801:Humans; D009154:Mutation / Q000235:genetics*; D015363:Quinolones / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D013678:Technology, Pharmaceutical
chemical_list: D000627:Aminophenols; D000631:Aminopyridines; D052117:Benzodioxoles; D018118:Chloride Channels; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor; C569105:lumacaftor